Scalable Synthesis of a Biaryl RAS ^G12C Cancer Inhibitor as a Single Atropdiastereomer

A scalable manufacturing route to AZD4747, a covalent KRAS G12C inhibitor for secondary CNS cancer, has been developed and demonstrated on multikilogram scale. A Pd(0)-catalyzed Suzuki–Miyaura coupling installed a sterically hindered tetra-ortho-substituted biaryl, initially giving a near-statistical atropdiastereomeric mixture, with optimization studies resulting in reduced Pd loading, improved robustness, and low impurity levels. A chiral chromatographic separation method used in the discovery route was replaced by a fractional crystallization separation approach using ( S )-O-acetylmandelic acid for salt formation. This enabled selective crystallization of the desired atropdiastereomeric ammonium salt in high stereochemical purity (99.8:0.2 dr ) on kilo-scale. Two-step installation of the N -acryloyl warhead was achieved via Schotten–Baumann amidation with 2-chloropropionyl chloride, followed by a base-promoted E1cB elimination reaction to yield >45 kg of AZD4747 that was suitable for clinical supply.